Contextual signaling in cancer

Abstract

The formation and maintenance of an organism is highly dependent on the orderly control of cell growth, differentiation, death, and migration. These processes are tightly regulated by signaling cascades in which a limited number of molecules dictate these cellular events. While these signaling pathways are highly conserved across species and cell types, the functional outcomes that result from their engagement are specified by the context in which they are activated. Using the Neurofibromatosis type-1 (NF1) cancer predisposition syndrome as an illustrative platform, we discuss how NF1/RAS signaling can create functional diversity at multiple levels (molecular, cellular, tissue, and genetic/genomic). As such, the ability of related molecules (e.g., K-RAS, H-RAS) to activate distinct effectors, as well as cell type- and tissue-specific differences in molecular composition and effector engagement, generate numerous unique functional effects. These variations, coupled with a multitude of extracellular cues and genomic/genetic changes that each modify the innate signaling properties of the cell, enable precise control of cellular physiology in both health and disease. Understanding these contextual influences is important when trying to dissect the underlying pathogenic mechanisms of cancer relevant to molecularly-targeted therapeutics.

Tumour growth and immune evasion as targets for a new strategy in advanced cancer

“…The deficiencies in the knowledge and the complexity of the mechanisms sustaining tumour growth are well known to the investigators and are also clearly mentioned in the updated article by Hanahan & Weinberg (2011). In a recent review (Smithson et al 2016), it has been suggested that 'signalling represents the language of the cell, where molecules (words) and cellular context (syntax) serve as units of informational content'; in addition, the authors stated that 'when we study signalling pathways in normal cells or in the setting of cancer, we often fail to consider how the cellular language conferred by these pathways is influenced by context, that is, the different extracellular signals present in the immediate milieu, the various adaptive responses that limit and promote intracellular signal transduction, the innate properties of distinct cell types responding to these cues, and the impact of epigenetic/genomic changes on the ultimate consequence of these informational signals'. They concluded that 'a deeper appreciation of contextual signalling may improve our understanding of the basic principles that govern development'.…”

Intracellular and intercellular signaling networks in cancer initiation, development and precision anti-cancer therapy

“…Our short summary and the papers of this special issue [25,29,30,33,36,39,42,52,57] highlight the promises and challenges of using signaling networks (including RAS-related signaling events) in the description of cancer initiation and development, metastasis and the emergence of drug resistance. As key messages we emphasize that…”

“…The approaches outlined above and in the contributions of this special issue [25,29,30,33,36,39,42,52,57] may overcome the current Nietzschean dilemma of cancer cell targeting: “what does not kill me makes me stronger” [60]. …”

“…These genomic approaches enable the design of personalized, high-precision anti-cancer therapies, as well as the “real-time” assessment of the development of drug resistance mechanisms. In the closing contribution of the three signaling network-related approaches David Gutmann and co-workers [42–44] use the Neurofibromatosis type-1 (NF1) cancer predisposition syndrome as an illustrative platform to show how RAS/NF1 signaling can create functional diversity both at the cellular and tissue levels. The NF1 protein (neurofibromin) is a RAS GTPase activating protein, thus its defect induces RAS hyper-activation.…”

“…However, its impact is highly context-dependent exhibiting a wide range of clinical variability. Gutmann’s and co-workers’ description of cell-type and tissue-specific differences in molecular composition of RAS/NF1-related signaling complexes, as well as of the contextual effects of multiple extracellular effectors [42] introduces the next level of complexity in cancer initiation and development: the cell-cell interactions of the cancer and stromal cell ecosystem described in the next section in detail.…”